Antidepressant azahetorocyclylmethyl derivatives of 7,8-dihydro-6H-5-oxa-1-aza-phenanthrene

ABSTRACT

Compounds of the formula  
                 
useful for the treatment of such as depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addition, sexual dysfunction (including premature ejaculation), and related illnesses.

This application claims priority from co-pending provisional applicationSer. No. 60/307,667, filed on Jul. 25, 2001, the entire disclosure ofwhich is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Major depressive disorder affects an estimated 340 million peopleworldwide. According to the World Health Organization, depression is thefourth greatest public health problem. If left untreated, the effects ofdepression can be devastating, robbing people of the energy ormotivation to perform everyday activities and, in some cases, leading tosuicide. Symptoms of the disorder include feelings of sadness oremptiness, lack of interest or pleasure in nearly all activities, andfeelings of worthlessness or inappropriate guilt. In addition to thepersonal costs of depression, the disorder also results in more than $40billion in annual costs in the United States alone, due to prematuredeath, lost productivity, and absenteeism.

Selective serotonin reuptake inhibitors (SSRIs) have had significantsuccess in treating depression and related illnesses and have becomeamong the most prescribed drugs. They nonetheless have a slow onset ofaction, often taking several weeks to produce their full therapeuticeffect. Furthermore, they are effective in fewer than two-thirds ofpatients.

SSRIs work by blocking the neuronal reuptake of serotonin, which tendsto increase the concentration of serotonin in the synaptic space, andthus increase the activation of postsynaptic serotonin receptors.However, although a single dose of an SSRI can inhibit the neuronalserotonin transporter and thus would be expected to increase synapticserotonin, long-term treatment is required before clinical improvementis achieved. It has been suggested that the SSRIs increase the serotoninlevels in the vicinity of the serotonergic cell bodies and that theexcess serotonin activates somatodendritic autoreceptors, 5-HT_(1A)receptors, causing a decrease in serotonin release in major forebrainareas. This negative feedback limits the increment of synaptic serotoninthat can be induced by antidepressants acutely. Over time, thesomatodendritic autoreceptors become desensitiized, allowing the fulleffect of the SSRI to be expressed in the forebrain. This time periodcorresponds to the latency for the onset of antidepressant activity[Perez, V., et al., The Lancet, 349:1594-1597 (1997)].

A 5-HT_(1A) agonist or partial agonist acts directly on postsynapticserotonin receptors to increase serotonergic neurotransmission duringthe latency period for the SSRI effect. Accordingly, the 5-HT_(1A)partial agonists buspirone and gepirone [Feiger, A., Psychopharmacol.Bull., 32 (4), 659-665 (1996), Wilcox, C., Psychopharmacol. Bull., 32(3), 335-342 (1996)] and the 5-HT_(1A) agonist flesinoxan [Grof, P.,International clinical Psychopharmacology, 8(3), 167-72 (1993)] haveshown efficacy in clinical trials for the treatment of depression.Furthermore, such agents would also stimulate the somatodendriticautoreceptors, thus hastening their desensitization and decreasing theSSRI latency period. An agent with a dual mechanism of antidepressantaction would be expected to have greater efficacy and thus reduce thenumber of patients refractory to treatment. Indeed, buspironeaugmentation has been shown to produce marked clinical improvement inpatients initally unresponsive to standard antidepressant therapy[Dimitriou, E., J. Clinical Psychopharmacol., 18(6), 465-469 (1998)].

Thus, it is highly desirable to provide improved compounds which bothinhibit serotonin reuptake and which are agonists or partial agonists ofthe 5-HT_(1A) receptor.

DESCRIPTION OF THE INVENTION

In accordance with this invention, there is provided a group of novelantidepressant agents of the formula:

wherein

-   -   R¹, R², R³, R⁴, R⁵, R⁸ and R⁹ are, independently, hydrogen,        hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six        carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms,        alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon        atoms, amino, mono- or di-alkylamino in which each alkyl group        has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or        alkanesulfonamido of 1 to 6 carbon atoms;    -   R⁶ and R⁷ are independently, hydrogen or alkyl of 1 to 6 carbon        atoms;    -   A dotted line represents an optional double bond;    -   A and D, taken together are —CR⁹═CH—, —N═CH—, or —CR⁷═N—;    -   Z is CR⁸ or N and    -   n is an integer 0, 1 or 2;    -   or a pharmaceutically acceptable salt thereof.

In some aspects of the invention it is preferred that R¹ is hydrogen,hydroxy, halo, trifluoromethyl, alkyl of one to six carbon atoms, alkoxyof one to six carbon atoms, amino, mono- or di-alkylamino in which eachalkyl group has one to six carbon atoms.

In other embodiments of the invention it is preferred that R² ishydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to sixcarbon atoms or alkoxy of one to six carbon atoms.

In still other embodiments of the invention, R³, R⁴ and R⁵ are,preferably independently selected from hydrogen, hydroxy, halo, cyano,carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to sixcarbon atoms. R³, R⁴, and R⁵ are still more preferably hydrogen, halogenor cyano.

In other preferred embodiments R¹, R², R³, R⁴ and R⁵ are, independentlyselected from hydrogen.

In still other preferred embodiments of the invention A=D is —CR⁹═CH—,and R⁹ is hydrogen.

Z is preferably CR⁸. When Z is CR⁸, R⁸ is preferably hydrogen, hydroxy,halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy ofone to six carbon atoms, and more preferably hydrogen, halogen or cyano

Of the compounds of Formula I, the preferred members are those in whichR¹ is hydrogen, hydroxy, halo, trifluoromethyl, alkyl of one to sixcarbon atoms, alkoxy of one to six carbon atoms, amino, mono- ordi-alkylamino in which each alkyl group has one to six carbon atoms; R²is hydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to sixcarbon atoms or alkoxy of one to six carbon atoms; Z is CR⁸; R³, R⁴, R⁵and R⁸ are, independently selected from hydrogen, hydroxy, halo, cyano,carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to sixcarbon atoms; n is an integer 0 or 1; A=D is CR⁹═CH; R⁹ is hydrogen; andR⁶ and the dotted line are defined as above.

Most preferred are those examples in which R¹ is defined as in theparagraph above, R² and R⁶ are hydrogen, R³, R⁴, R⁵ and R⁸ are,independently selected from hydrogen, halo or cyano, n is 0 and thedotted line represents a double bond.

This invention relates to both the R and S stereoisomers of theaminomethyl-7,8-dihydro-6H-5-oxa-1-aza-phenanthrene, as well as tomixtures of the R and S stereoisomers. Throughout this application, thename of the product of this invention, where the absolute configurationof the aminomethyl-7,8-dihydro-6H-5-oxa-1-aza-phenanthrene is notindicated, is intended to embrace the individual R and S enantiomers aswell as mixtures of the two. In some preferred embodiments of thepresent invention the R stereoisomer is preferred.

Where a stereoisomer is preferred, it may in some embodiments beprovided substantially free of the corresponding enantiomer. Thus, anenantiomer substantially free of the corresponding enantiomer refers toa compound which is isolated or separated via separation techniques orprepared free of the corresponding enantiomer. Substantially free asused herein means that the compound is made up of a significantlygreater proportion of one stereoisomer. In preferred embodiments thecompound is made up of at least about 90% by weight of a preferredstereoisomer. In other embodiments of the invention, the compound ismade up of at least about 99% by weight of a preferred stereoisomer.Preferred stereoisomers may be isolated from racemic mixtures by anymethod known to those skilled in the art, including high performanceliquid chromatography (HPLC) and the formation and crystallization ofchiral salts or prepared by methods described herein. See, for example,Jacques, et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725(1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill,NY, 1962); Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972).

It is further recognized that tautomers of the claimed compounds mayexist, for instance, when R¹ is hydroxy, a tautomeric form may exist.The present invention thus encompasses tautomeric forms of compounds ofthe present invention.

Alkyl as used herein refers to an aliphatic hydrocarbon chain andincludes straight and branched chains such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1to 3 carbon atoms.

Alkanamido as used herein refers to the group R—C(═O)—NH— where R is analkyl group of 1 to 5 carbon atoms.

Alkanoyloxy as used herein refers to the group R—C(═O)—O— where R is analkyl group of 1 to 5 carbon atoms.

Alkanesulfonamido as used herein refers to the group R—S(O)₂—NH— where Ris an alkyl group of 1 to 6 carbon atoms.

Alkoxy as used herein refers to the group R—O— where R is an alkyl groupof 1 to 6 carbon atoms.

Carboxamido as used herein refers to the group —CO—NH₂.

Carboalkoxy as used herein refers to the group R—O—C(═O)— where R is analkyl group of 1 to 5 carbon atoms.

Halogen (or halo) as used herein refers to chlorine, bromine, fluorineand iodine.

Pharmaceutically acceptable salts are those derived from such organicand inorganic acids as: acetic, lactic, citric, cinnamic, tartaric,succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,benzoic, and similarly known acceptable acids.

Specific compounds of the present invention are:

-   6-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene;-   (6S)-6-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene;    and-   (6R)-6-[4-(5-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene;    and pharmaceutical salts thereof.

Further in accordance with the present invention is provided novelintermediates of the formula:

wherein

-   -   R¹ and R² are, independently, hydrogen, hydroxy, halo, cyano,        carboxamido, carboalkoxy of two to six carbon atoms,        trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6        carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono-        or di-alkylamino in which each alkyl group has 1 to 6 carbon        atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido        of 1 to 6 carbon atoms;    -   X is halogen, hydroxy, alkylsulfonate of 1 to 6 carbon atoms,        trifluoromethanesulfonate or benzenesulfonate, in which the        benzene ring is optionally substituted with halogen, hydroxy,        nitro, trifluoromethyl, cyano, alkyl of 1 to 6 carbon atoms or        alkoxy of 1 to 6 carbon atoms.

Compounds of Formula II are particularly useful for the production ofagents of Formula I.

Specific compounds of Formula II include:

-   -   Toluene-4-sulfonic acid        7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester;    -   (6S)-Toluene-4-sulfonic acid        7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl-methyl ester; and    -   (6R)-Toluene-4-sulfonic acid        7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl-methyl ester.

Unless otherwise noted, the variables used in the following schemes areas defined above.

The 6-azaheterocyclylmethyl-7,8-dihydro-6H-5-oxa-1-aza-phenanthrenes inwhich R¹ is H are prepared as illustrated below in Scheme I.Specifically, the appropriately substituted4-acetamido-2-hydroxyacetophenone (1) is alkylated with allyl bromide inthe presence of a suitable base such as sodium

hydride to produce (2) and then heated in a high boiling solvent such asdimethylaniline to effect a Claisen rearrangement. The resulting4-acetamido-3-allyl-2-hydroxyacetophenone (3) is then converted to thechromone under standard conditions involving condensation with diethyloxalate and sodium in ethanol, followed by cyclization via refluxing inethanol in the presence of an acid such as hydrochloric acid. Theresulting 8-allyl-7-amino-4-oxo-4H-chromene-2-carboxylic acid ethylester (4) is re-protected as the trifluoroacetamide by treatment withtrifluoroacetic anhydride and a tertiary base such asdiisopropylethylamine. The allyl group is then isomerized by treatmentwith catalytic bis-acetonitrile palladium (II) chloride in refluxingmethylene chloride or benzene to form (5). Allylic oxidation viatreatment with an excess of selenium dioxide in refluxing dioxan isaccompanied by cyclization and deprotection to afford the5-oxa-1-aza-phenanthrene ring system (6), which characterizes thecompounds of the invention. Sequential reduction of the chromone, viatreatment with hydrogen in the presence of a catalyst such as 20%palladium hydroxide on carbon, and the carboethoxy group, via lithiumborohydride in tetrahydrofuran, is accompanied by reduction of thequinoline (7) and necessitates re-aromatization via treatment with anoxidant such as manganese dioxide. The resulting primary alcohol isconverted to the tosylate (IIa) by reaction with p-toluenesulfonylchloride in the presence of a tertiary amine or alternatively to ahalide by reaction with carbon tetrabromide or carbon tetrachloride incombination with triphenylphosphine. Replacement of the tosylate orhalide with the appropriately substituted azaheterocycle in some highboiling solvent such as dimethyl sulfoxide gives the title compounds ofthe invention.

Compounds of the invention in which R¹ is alkyl may be prepared from the8-propenyl-7-trifluoroacetamido-4-oxo-4H-chromene-2-carboxylic acidethyl ester described above in accordance with Scheme II. The rearrangedolefin (5) is treated with osmium tetroxide and sodium periodate to givethe o-trifluoro-acetamidobenzaldehyde (8). Condensation with theappropriate triphenyl-phosphorylidene ketone under Wittig conditionsgives the o-trifluoroacetamidostyryl ketone (9), which upon treatmentwith acid cyclizes to give the 5-oxa-1-aza-phenanthrene ring system ofthe title compounds (10). Reduction, re-aromatization and tosylation asabove gives the 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-methyltosylate.Replacement of the tosylate with the appropriately substitutedazaheterocycle as above gives the title compounds of the invention.Substitution of trimethyl phosphonoacetate for thetriphenylphosphorylidene ketone in the Wittig procedure above, followedby cyclization in acid gives the compounds of the invention in which R¹is hydroxy. Alkylation of this hydroxy derivative by a suitable alkylhalide or tosylate in the presence of base gives the compounds of theinvention in which R¹ is alkoxy. Treatment of the hydroxy derivativewith an inorganic acid chloride such as phosphoryl chloride or bromidegives the compounds of the invention in which R¹ is halo. Substitutionof diethyl cyanomethylphosphonate for the triphenylphosphorylideneketone in the Wittig procedure above, followed by cyclization in acidgives the compounds of the invention in which R¹ is amino.

Compounds of the invention in which R² is attached to position 10 of the7,8-dihydro-6H-5-oxa-1-aza-phenanthrene may be alternatively prepared bya variation of the Skraup quinoline synthesis according to the SchemeIII below. The appropriately substituted chroman methyltosylate (11) isnitrated under standard conditions with nitric acid in a solvent such asdichloroethane and the resulting nitro

compound (12) reduced by treatment with hydrogen in the presence of acatalyst such as platinum on sulfide carbon. Treatment of the resultinganiline (13) with acrolein in the presence of hydrogen chloride and anoxidant such as p-chloranil or naphthoquinone gives the corresponding7,8-dihydro-6H-5-oxa-1-aza-phenanthrene (IIa). Replacement of thetosylate with the appropriately substituted azaheterocycle as abovegives the title compounds of the invention.

The compounds of the invention in which R¹ and R² are hydrogen may bealternatively prepared as shown in Scheme IV below. The appropriatelyprotected (TBS represents t-butyidimethylsilyl, Boc is t-butoxycarbonyl)7-amino-8-methyl-chroman-2-methanol (14) is metallated with sec-butyllithium and alkylated with allyl bromide. The olefin (15) is thentreated with osmium tetroxide and sodium periodate as described above togive the aldehyde, which spontaneously cyclizes to give the protectedcyclic aminal. Following deprotection of the primary alcohol withtetra-n-butylammonium fluoride (TBAF) to provide (16), dehydration andaromatization is effected by a period of heating in o-dichlorobenzene.The resulting (7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol(IIb) is converted to the compounds of the invention as described above.

The acetophenones, chromans and azaheterocycles appropriate to the abovechemistry are known compounds or they can be prepared by one schooled inthe art. The compounds of the invention may be resolved into theirenantiomers by conventional methods involving partial crystallization ofa diastereomeric salt, separation on a chiral HPLC column or enzymaticresolution of a suitable intermediate or, in the case of the compoundsof the invention in which R¹ and R² are hydrogen, the individualenantiomers may be prepared directly by substitution of the known[Tetrahedron 54(25) 7081, (1998)] (R)- or(S)-[2-(t-butyl-dimethyl-silanyloxy-methyl)-8-methyl-chroman-7-yl]-carbamicacid t-butyl ester for the racemic starting material in the procedureabove.

Like the antidepressants fluoxetine, paroxetine and sertraline, thecompounds of this invention have the ability to potently block thereuptake of the brain neurotransmitter serotonin. They are thus usefulfor the treatment of depression and other diseases commonly treated bythe administration of serotonin selective reuptake inhibitor (SSRI)antidepressants, such as obsessive compulsive disorder, panic attacks,generalized anxiety disorder, social anxiety disorder, sexualdysfunction, eating disorders, obesity, addictive disorders caused byethanol or cocaine abuse and related illnesses. Moreover, the compoundsof this invention have affinity for agonist or partial agonist activityat brain 5-HT_(1A) serotonin receptors. The 5-HT_(1A) partial agonistsbuspirone and gepirone have demonstrated anxiolytic and antidepressantproperties in clinical trials and the 5-HT_(1A) full agonist flesinoxanhas been shown to be an effective antidepressant. The compounds of theinvention are thus exceedingly interesting and useful for treatingdepressive illnesses.

A protocol similar to that used by Cheetham et. al. (Neuropharmacol.32:737, 1993) was used to determine the affinity of the compounds of theinvention for the serotonin transporter. The compound's ability todisplace ³H-paroxetine from male rat frontal cortical membranes wasdetermined using a Tom Tech filtration device to separate bound fromfree ³H-paroxetine and a Wallac 1205 Beta Plate® counter to quantitatebound radioactivity. K_(i)'s thus determined for standard clinicalantidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and67.6 nM for zimelidine. A strong correlation has been found between³H-paroxetine binding in rat frontal cortex and ³H-serotonin uptakeinhibition.

High affinity for the serotonin 5-HT_(1A) receptor was established bytesting the claimed compound's ability to displace [³H] 8-OHDPAT(dipropylaminotetralin) from the 5-HT_(1A) serotonin receptor followinga modification of the procedure of Hall et al., J. Neurochem. 44, 1685(1985) which utilizes CHO cells stably transfected with human 5-HT_(1A)receptors. The 5-HT_(1A) affinities for the compounds of the inventionare reported below as K_(i)'s.

Agonist activity at 5-HT_(1A) receptors was established by using a³⁵S-GTPγS binding assay similar to that used by Lazareno and Birdsall(Br. J. Pharmacol. 109: 1120, 1993), in which the test compound'sability to affect the binding of ³⁵S-GTPγS to membranes containingcloned human 5-HT_(1A) receptors was determined. Agonists produce anincrease in binding whereas antagonists produce no increase but ratherreverse the effects of the standard agonist 8-OHDPAT. The testcompound's maximum stimulatory effect is represented as the E_(max),while its potency is defined by the EC₅₀.

The results of the three standard experimental test procedures describedin the preceding three paragraphs were as follows:

5-HT Transporter Affinity 5-HT_(1A) Receptor Affinity 5-HT_(1A) FunctionCompound KI (nM) KI (nM) EC₅₀ (nM) (E_(max)) Example 1 8.00 60.92 103.0(49.0) Example 2 5.96 88.60     (5.00) Example 3 6.00 82.32  78.9 (52.0)

Hence. the compounds of this invention are combined serotonin reuptakeinhibitors/5-HT_(1A) agonists and are useful for the treatment ofdepression and other conditions related to or affected by the reuptakeof serotonin and by the serotonin 1A receptor, such as depression(including but not limited to major depressive disorder, childhooddepression and dysthymia), anxiety, panic disorder, post-traumaticstress disorder, premenstrual dysphoric disorder (also known aspre-menstrual syndrome), attention deficit disorder (with and withouthyperactivity), obsessive compulsive disorder (includingtrichotillomania), social anxiety disorder, generalized anxietydisorder, obesity, eating disorders such as anorexia nervosa, bulimianervosa, vasomotor flushing, cocaine and alcohol addition, sexualdysfunction (including premature ejaculation), and related illnesses.

Thus the present invention provides methods of treating, preventing,inhibiting or alleviating each of the maladies listed above in a mammal,preferably in a human, the methods comprising providing apharmaceutically effective amount of a compound of this invention to themammal in need thereof.

Also encompassed by the present invention are pharmaceuticalcompositions for treating or controlling disease states or conditions ofthe central nervous system comprising at least one compound of FormulaI, mixtures thereof, and or pharmaceutical salts thereof, and apharmaceutically acceptable carrier therefore. Such compositions areprepared in accordance with acceptable pharmaceutical procedures, suchas described in Remingtons Pharmaceutical Sciences, 17th edition, ed.Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).Pharmaceutical acceptable carriers are those that are compatible withthe other ingredients in the formulation and biologically acceptable.

The compounds of this invention may be administered orally orparenterally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders ortablet-disintegrating agents or an encapsulating material. In powders,the carrier is a finely divided solid which is in admixture with thefinely divided active ingredient. In tablets, the active ingredient ismixed with a carrier having the necessary compression properties insuitable proportions and compacted in the shape and size desired. Thepowders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions,emulsions, syrups and elixirs. The active ingredient of this inventioncan be dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fat. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (particularlycontaining additives as above e.g. cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are used insterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. Oral administration may be either liquid orsolid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets, capsules, powders, solutions, suspensions, emulsions,granules, or suppositories. In such form, the composition is sub-dividedin unit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example packetedpowders, vials, ampoules, prefixed syringes or sachets containingliquids. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compositions inpackage form.

The amount provided to a patient will vary depending upon what is beingadministered, the purpose of the administration, such as prophylaxis ortherapy, and the state of the patient, the manner of administration, andthe like. In therapeutic applications, compounds of the presentinvention are provided to a patient already suffering from a disease inan amount sufficient to cure or at least partially ameliorate thesymptoms of the disease and its complications. An amount adequate toaccomplish this is defined as a “therapeutically effective amount.” Thedosage to be used in the treatment of a specific case must besubjectively determined by the attending physician. The variablesinvolved include the specific condition and the size, age and responsepattern of the patient. Generally, a starting dose is about 5 mg per daywith gradual increase in the daily dose to about 150 mg per day, toprovide the desired dosage level in the human.

Provide as used herein means either directly administering a compound orcomposition of the present invention, or administering a prodrug,derivative or analog which will form an equivalent amount of the activecompound or substance within the body.

The present invention includes prodrugs of compounds of Formula I.“Prodrug”, as used herein means a compound which is convertible in vivoby metabolic means (e.g. by hydrolysis) to a compound of Formula I.Various forms of prodrugs are known in the art, for example, asdiscussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985);Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press(1985); Krogsgaard-Larsen, et al., (ed). “Design and Application ofProdrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991), Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975).

The following examples illustrate the production of representativecompounds of this invention.

Intermediate 18-Allyl-4-oxo-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylicacid ethyl ester

To 8-allyl-7-amino-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (8.6g, 32 mmole) in 400 mL of methylene chloride was added firstN,N-diisopropyl-ethylamine (6.5 g, 50 mmole) and then, while cooling themixture in an ice bath, trifluoroacetic anhydride (10.5 g, 50 mmole).The mixture was stirred at room temperature for one hour, then washedwith 200 mL portions of 2 N aqueous HCl, saturated aqueous sodiumbicarbonate, and saturated brine, dried over sodium sulfate, filteredand concentrated in vacuum to give 12.2 g of the title compound as apale yellow solid, m.p. 136-137° C.

Elemental Analysis for: C₁₇H₁₄F₃NO₅

Calc'd: C, 55.29; H, 3.82; N, 3.79

Found: C, 55.28; H, 3.79; N, 3.76

Intermediate 24-Oxo-8-propenyl-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylicacid ethyl ester

To8-allyl-4-oxo-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylicacid ethyl ester (12.2 g, 32 mmole) in 500 mL of methylene chloride wasadded 1.5 g (5.8 mmole) of bis(acetonitrile) palladium (II) chloride.The mixture was refluxed under nitrogen for 24 hours. Upon cooling toroom temperature, the mixture was filtered through 75 g of silica gel,with additional methylene chloride as needed to fully elute the product.Concentration in vacuum gave 10.4 g of the title compound as a yellowsolid, m.p. 140-141° C.

Elemental Analysis for: C₁₇H₁₄F₃NO₅

Calc'd: C, 55.29; H, 3.82; N, 3.79

Found: C, 55.24; H, 3.89; N, 3.75

INTERMEDIATE 3 8-Oxo-8H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethylester

To4-oxo-8-propenyl-7-(2,2,2-trifluoro-acetylamino)-4H-chromene-2-carboxylicacid ethyl ester (3.7 g, 10 mmole) in 100 mL of dioxan was added 4.4 g(40 mmole) of selenium dioxide. The mixture was refluxed under nitrogenfor 5 hours. An additional 1.0 g of selenium dioxide was added andreflux continued for 8 hours. After the reaction had cooled, 500 mL ofwater was added and the mixture was extracted with first 300 mL and then200 mL of ethyl acetate. The combined organic extracts were washed withwater and with saturated brine, dried over sodium sulfate, filtered andevaporated in vacuum to give 2.0 g of the title compound as a yellowsolid. An analytically pure sample of yellow solid (m.p. 146-147° C.)was obtained by column chromatography on silica gel with 0-5% ethylacetate/methylene chloride as eluant.

Elemental Analysis for: C₁₅H₁₁NO₄.1.1H₂O

Calc'd: C, 62.33; H, 4.60; N, 4.85

Found: C, 62.09; H, 4.15; N, 4.79

Intermediate 4(1,3,4,6,7,8-Hexahydro-2H-5-oxa-1-aza-phenanthren-6-yl)-methanol

8-Oxo-8H-5-oxa-1-aza-phenanthrene-6-carboxylic acid ethyl ester (2.0 g,7.4 mmole) was dissolved in 200 mL of ethanol and 0.50 g of 20%palladium hydroxide on carbon added. The mixture was treated with 60 psiof hydrogen on a Parr apparatus for 48 hours, then filtered throughcelite and concentrated in vacuum. Thin layer chromatography on silicagel vs. a starting material standard indicated that the reaction wasincomplete. The material was redissolved in 150 mL of acetic acid, 0.50g of 20% palladium hydroxide on carbon added, and the mixture againtreated with 60 psi of hydrogen for 48 hours. It was then filteredthrough celite, concentrated in vacuum and column chromatographed onsilica gel with 2% ethanol in chloroform as eluant to give 0.80 g of1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthrene-6-carboxylic acidethyl ester. ¹H-NMR (CDCl₃): doublet 6.65 δ (1H); doublet 6.1 δ (1H);multiplet 4.7 δ (1H); quartet 4.25 δ (2H); broad singlet 3.65 δ (1H);multiplet 3.2 δ (2H); multiplet 2.65 δ (4H); multiplet 2.2 δ (2H);multiplet 1.95 δ (2H); triplet 1.25 δ (3H).

To 1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthrene-6-carboxylic acidethyl ester (0.80 g, 3.1 mmole) in 25 mL of tetrahydrofuran was added0.22 g (10 mmole) of lithium borohydride. The mixture was stirred for 48hours at room temperature. Methanol (5 mL) was added and stirring atroom temperature continued for an additional hour. The mixture was thendiluted to 300 mL with ethyl acetate and washed with 100 mL portions ofwater and saturated brine and dried over sodium sulfate. Filtration andconcentration in vacuum gave 0.83 g of the title compound as a whitesolid. ¹H-NMR (CDCl₃): doublet 6.65 δ (1H); doublet 6.1 δ (1H);multiplet 4.1 δ (1H); multiplet 3.8 δ (2H); multiplet 3.2δ (2H); broadsinglet 2.8 δ (1H); multiplet 2.55 δ (4H); multiplet 1.9 δ (2H);multiplet 1.2 δ (2H).

Intermediate 5 (7,8-Dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol

To (1,3,4,6,7,8-hexahydro-2H-5-oxa-1-aza-phenanthren-6-yl)-methanol(0.90 g, 4.0 mmole) in 150 mL of toluene was added 1.8 g (20 mmole) ofmanganese dioxide. The mixture was refluxed under nitrogen for 24 hours.It was then filtered through celite, concentrated in vacuum and columnchromatographed on silica gel with 0-2% methanol/chloroform as eluant.Concentration of the product fractions in vacuum gave 0.30 g of thetitle compound as an orange oil. ¹H-NMR (CDCl₃): doublet 8.8 δ (1H);doublet 8.4 δ (1H); doublet 7.6 δ (1H); doublet 7.35 δ (1H); doublet ofdoublets 7.25 δ (1H); multiplet 4.25 δ (1H); multiplet 3.95 δ (2H);multiplet 2.9 δ (2H); multiplet 2.05 δ (2H).

Intermediate 6 Toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester

(7,8-Dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.27 g, 1.3mmole) was dissolved in 75 mL of methylene chloride andp-toluenesulfonyl chloride (0.60 g, 3.1 mmole) added. The mixture wasplaced in an ice/isopropanol bath and first N,N-diisopropylethylamine(0.55 mL, 3.1 mmole) and then N,N-dimethyaminopyridine added. Themixture was allowed to stir under nitrogen for 5 days. It was washedwith 150 mL portions of 2 N aqueous HCl, saturated aqueous sodiumbicarbonate and saturated brine, dried over magnesium sulfate, filteredand concentrated in vacuum to an orange oil. Column chromatography onsilica gel with 0-5% methanol/methylene chloride gave 0.22 g of thetitle compound. ¹H-NMR (CDCl₃): doublet 8.8 δ (1H); doublet 8.25 δ (1H);doublet 7.8 δ (2H); doublet 7.6 δ (1H); multiplet 7.3 δ (4H); multiplet4.4 δ (1H); doublet 4.3 δ (2H); multiplet 2.9 δ (2H); singlet 2.4 δ(3H); multiplet 2.0 δ (2H).

EXAMPLE 16-[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene

Toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.22 g, 1.67mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (4.0 g,1.8 mmole) were combined in 200 mL of DMSO and heated at 75-80° C. undernitrogen for 13 hours. After cooling to room temperature, the mixturewas partitioned between 400 mL each of ethyl acetate and saturatedsodium bicarbonate solution. The organic phase was removed, washed withsaturated brine, dried over magnesium sulfate and concentrated to an oilin vacuum. This was column chromatographed on silica gel using firstmethylene chloride to elute impurities and then 5% methanol in methylenechloride to elute the product, 0.19 g of a yellow oil. The oil wasrecrystallized from isopropanol with the addition of 0.05 g of oxalicacid to give 0.043 g of the title compound as a yellow solid (m.p. 148°C.).

Elemental Analysis for: C₂₆H₂₄FN₃O.C₂H₂O₄.H₂O

Calc'd: C, 58.92; H, 4.92; N, 6.83

Found: C, 58.56; H, 4.45; N, 6.62

Intermediate 7(2S)-[8-But-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamicacid tert-butyl ester

To a solution of(2S)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methyl-chroman-7-yl]-carbamicacid tert-butyl ester (0.41 g, 1.0 mmole) in anhydrous tetrahydrofuran(20 mL) containing 0.010 g of 1,10-phenanthroline at −40° C. was slowlyadded 2.4 equivalents of 1.3 M s-butyl lithium. After 1 equivalent ofs-butyl lithium had been added, the deep red color of the indicatorbecame apparent. The reaction was allowed to stand for 1.5 hours afterwhich allyl bromide (0.24 g, 2.0 mmole) was added. After an additional 4hours the reaction was quenched with water (4 mL). The reaction mixturewas diluted with ether (250 mL) and washed with saturated aqueous sodiumbicarbonate (50 mL). The organic layer was separated and the solventremoved under vacuum. Column chromatography on silica gel (5% ethylacetate/hexane) afforded 0.38 g (85%) of the title compound as an oil,[M+H]⁺: 448, [α]²⁵ _(D)=+34.0° (c=1.03, THF).

Elemental Analysis for: C₂₅H₄₁NO₄Si.0.15 CH₂Cl₂

Calc'd: C, 65.61; H, 9.04; N 3.04

Found: C, 65.61, H, 9.00, N 3.02

Intermediate 8(6S)-2-Hydroxy-6-hydroxymethyl-3,4,7,8-tetrahydro-2H,6H-5-oxa-1-aza-phenanthrene-1-carboxylicacid tert-butyl ester

To a solution of(2S)-[8-but-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamicacid tert-butyl ester (0.33 g, 0.74 mmole) in anhydrous tetrahydrofuran(15 mL) and water (3 mL) at 0° C. was added osmium tetroxide (0.1 mL, 5%in water), followed by sodium periodate (0.47 g, 2.2 mmole). The mixturewas stirred for 48 hours. The solution was diluted with ethyl acetateand the organic layer was washed with water, dried over Na₂SO₄,filtered, and the solvent evaporated in vacuum. Column chromatography onsilica gel (80% ethyl acetate/hexane) afforded 0.19 g (76%) of the titlecompound as an oil, the t-butyldimethylsilyl protecting group havingbeen cleaved in the course of the reaction. [α]²⁵ _(D)=+40.66° (c=7.7,DMSO)

Elemental analysis for: C₁₈H₂₅NO₅

Calc'd: C, 64.46; H, 7.51; N 4.18

Found: C, 68.18; H, 7.62; N 4.06

Intermediate 9(6S)-(7,8-Dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol

A solution of(6S)-2-hydroxy-6-hydroxymethyl-3,4,7,8-tetrahydro-2H,6H-5-oxa-1-aza-phenanthrene-1-carboxylicacid tert-butyl ester (0.33 mg, 1.0 mmole) in o-dichlorobenzene (15 mL)was stirred at 180° C. for 4 hours. The solvent was removed in vacuum.The residue was purified by column chromatography on silica gel (50%methylene chloride/hexane) to afford 0.15 g (71%) of the title compoundas a solid, mp 128° C., [α]²⁵ _(D)=+74.19° (c=7.7, DMSO).

Elemental analysis for: C₁₃H₁₃NO₂.0.15H₂O

Calc'd: C, 71.64; H, 6.15; N 6.43

Found: C, 71.63; H, 6.12; N 6.33

Intermediate 10 (6S)-Toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester

A solution of(6S)-(7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.14 g,0.65 mmole) and p-toluenesulfonyl chloride (0.25 g, 1.3 mmole) inanhydrous pyridine (50 mL) was allowed to stir for 24 hours and then thesolvent was removed in vacuum. The residue was dissolved in ethylacetate (50 mL) and washed with water (3×30 mL). The organic layer wasdried over sodium sulfate and filtered, and the solvent was removedunder vacuum. Column chromatography on silica gel (50% methylenechloride/hexane) afforded 0.23 g (96%) of the title compound as a solid,mp 123° C., [α]²⁵ _(D)=+51.22° (4.92, CHCl₃).

Elemental analysis for: C₂₀H₁₉NO₄S.0.1 CH₂Cl₂

Calc'd: C, 63.88; H, 5.12; N 3.71

Found: C, 63.55; H, 5.00; N 3.60

EXAMPLE 2(6S)-6-[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene

A solution of (6S)-toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.12 g, 0.33mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.14g, 0.65 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2hours. The reaction mixture was then poured into chloroform (100 mL) andwashed with water (3×40 mL). The organic layer was dried over sodiumsulfate and filtered, and the solvent was removed under vacuum. Columnchromatography on silica gel (5% methanol/ethyl acetate) afforded 0.083g (62%) of the title compound. The oxalate salt was prepared in ethylacetate and ethanol and had mp 210° C. and [α]²⁵ _(D)=+71.43° (c=4.68,DMSO).

Elemental analysis for: C₂₆H₂₄FN₃O.2 C₂H₂O₄

Calc'd: C, 60.64; H, 4.75; N, 7.07

Found: C, 60.93; H, 4.80; N, 7.29

Intermediate 11(2R)-[8-But-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamicacid tert-butyl ester

To a solution of(2R)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methyl-chroman-7-yl]-carbamicacid tert-butyl ester (0.41 g, 1 mmole) in anhydrous tetrahydrofuran (20mL) containing 10 mg of 1,10-phenanthroline at −40° C. was slowly added2.4 equivalents of 1.3 M s-butyl lithium. After 1 equivalent of s-butyllithium had been added, the deep red color of the indicator becameapparent. The reaction was allowed to stand for 1.5 hours, after whichallyl bromide (0.24 g, 2.0 mmole) was added. The reaction was allowed tostand for an additional 4 hours and then was quenched with water (4 mL).The reaction mixture was next diluted with ether (250 mL) and washedwith saturated aqueous sodium bicarbonate (50 mL). The organic layer wasseparated and the solvent removed under vacuum. Column chromatography onsilica gel (5% methylene chloride/hexane) afforded 0.37 g (75%) of thetitle compound as an oil, [α]²⁵ _(D)=−32.42° (3.7, THF).

Elemental analysis for: C₂₅H₄₁NO₄Si.0.05 CH₂Cl₂

Calc'd: C, 66.57; H, 9.16; N 3.09

Found: C, 66.46; H, 9.31; N 2.97.

Intermediate 12(6R)-6-(tert-Butyl-dimethyl-silanyloxymethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H,6H-5-oxa-1-aza-phenanthrene-1-carboxylicacid tert-butyl ester

To a solution of(2R)-[8-but-3-enyl-2-(tert-butyl-dimethyl-silanyloxymethyl)-chroman-7-yl]-carbamicacid tert-butyl ester (3.6 g, 8.0 mmole) in tetrahydrofuran (150 mL) andwater (15 mL) at 0° C. was added osmium tetroxide (0.4 mL, 5% in water),followed by sodium periodate (5.16 g, 24 mmole). The mixture was stirredfor 6 hours. The solution was diluted with ethyl acetate and the organiclayer was washed with water, dried over sodium sulfate, filtered, andthe solvent evaporated in vacuum. Column chromatography on silica gel(10% ethyl acetate/hexane) afforded 2.92 g (81%) of the title compoundas an oil, [α]²⁵ _(D)=−36.75° (4.9, THF).

Elemental analysis for: C₂₄H₃₉NO₅Si

Calc'd: C, 64.11; H, 8.79; N, 3.11

Found: C, 63.64; H, 8.09; N, 2.90

Intermediate 13(6R)-6-(tert-Butyl-dimethyl-silanyloxymethyl)-7,8-dihydro-6H-5-oxa-1-aza-phenanthrene

A solution of(6R)-6-(tert-butyl-dimethyl-silanyloxymethyl)-2-hydroxy-3,4,7,8-tetrahydro-2H,6H-5-oxa-1-aza-phenanthrene-1-carboxylicacid tert-butyl ester (0.45 g, 1.0 mmole) in o-dichlorobenzene (150 mL)was stirred at 180° C. for 4 hours. The solvent was removed in vacuum.The residue was purified by column chromatography on silica gel (10%methylene chloride/hexane) to afford 0.23 g (70%) of the title compoundas an oil, [α]²⁵ _(D)=−61.94° (c=10.7, THF).

Elemental analysis for: C₁₉H₂₇NO₂Si.0.1 CH₂Cl₂

Calc'd: C, 67.87; H, 8.11; N, 4.14

Found: C, 67.69; H, 7.89; N, 4.05

Intermediate 14(6R)-(7,8-Dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol

To a solution of(6R)-6-(tert-butyl-dimethyl-silanyloxymethyl)-7,8-dihydro-6H-5-oxa-1-aza-phenanthrene(0.60 g, 1.82 mmole) in tetrahydrofuran (50 mL) was addedtetra-n-butylammonium fluoride (2 mL, 1 M in THF). The reaction mixturewas stirred for 20 minutes, then diluted with ethyl acetate and washedwith water, dried over sodium sulfate, and the solvent removed invacuum. The residue was purified by column chromatography on silica gel(50% methylene chloride/hexane) to afford 0.38 g (98%) of the titlecompound as a white solid, mp 128° C., [α]²⁵ _(D)=+113.81° (c=5.9,CHCl₃).

Elemental analysis for: C₁₃H₁₃NO₂.0.2 C₆H₁₄+0.1 CH₂Cl₂

Calc'd: C, 71.64; H, 6.15; N, 6.43

Found: C, 71.63; H, 6.12; N, 6.33

Intermediate 15 (6R)-Toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester

A solution of(6R)-(7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-yl)-methanol (0.38 g, 1.8mmole) and p-toluenesulfonyl chloride (0.67 g, 3.5 mmole) in anhydrouspyridine (50 mL) was allowed to stir for 24 hours and then the solventwas removed in vacuum. The residue was dissolved in ethyl acetate (50mL) and washed with water (3×30 mL). The organic layer was dried oversodium sulfate and filtered, and the solvent was removed under vacuum.Column chromatography on silica gel (50% methylene chloride/hexane)afforded 0.62 g (95%) of the title compound as a solid, mp 123° C.,[α]²⁵ _(D)=−27.71° (c=5.0, CHCl₃).

Elemental analysis for: C₂₀H₁₉NO₄S.0.05 CH₂Cl₂

Calc'd: C, 64.44; H, 5.15; N, 3.74

Found: C, 64.13; H, 5.00; N, 3.76

EXAMPLE 3(6R)-6-[4-(5-Fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-7,8-dihydro-6H-5-oxa-1aza-phenanthrene

A solution of (6R)-toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.17 g, 0.47mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.20g, 0.94 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2hours. The reaction mixture was then poured into chloroform (100 mL) andwashed with water (3×40 mL). The organic layer was dried over sodiumsulfate and filtered, and the solvent was removed under vacuum. Columnchromatography on silica gel (5% methanol/ethyl acetate) afforded 0.11 g(55%) of the title compound. The fumarate salt was prepared in ethylacetate and isopropyl alcohol and had mp 210° C. and [α]²⁵ _(D)=−60.03°(c=4.5, DMSO).

Elemental analysis for: C₂₆H₂₄FN₃O.C₄H₄O₄.H₂O

Calc'd: C, 65.61; H, 5.77; N, 7.42

Found: C, 65.28; H, 5.43; N, 7.03

1-14. (canceled)
 15. An intermediate of the formula

wherein R¹ and R² are, independently, hydrogen, hydroxy, halo, cyano,carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl,alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxyof 2 to 6 carbon atoms, amino, mono-or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; and X is halogen, hydroxy,alkylsulfonate of 1 to 6 carbon atoms, trifluoromethanesulfonate orbenzenesulfonate, in which the benzene ring is optionally substitutedwith halogen, hydroxy, nitro, trifluoromethyl, cyano, alkyl of 1 to 6carbon atoms or alkoxy of 1 to 6 carbon atoms.
 16. A compound of claim15 which is: Toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester;(6S)-Toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester; or(6R)-Toluene-4-sulfonic acid7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester. 17-20.(canceled)